System and method for determination of transpulmonary pressure in a patient connected to a breathing apparatus

ABSTRACT

A breathing apparatus ( 1 ) is disclosed that is adapted to determine a transpulmonary pressure in a patient ( 125 ) when connected to said breathing apparatus. A control unit ( 105 ) is operable to set a first mode of operation for ventilating said patient with a first Positive End Expiratory Pressure (PEEP) level; set a second mode of operation for ventilating said patient with a second PEEP level starting from said first PEEP level; and determine said transpulmonary pressure (Ptp) based on a change in end-expiratory lung volume (ΔEELV) and a difference between said first PEEP level and said second PEEP level (ΔPEEP). Furthermore, a method and computer program are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Phase under 35 U.S.C. §371 ofInternational Application PCT/EP2011/060264, filed on Jun. 20, 2011,designating the United States of America, and published in the EnglishLanguage as WO 2011/157855 on Dec. 12, 2011, which claims priority to EPPatent Application No. EP 10166587.5, filed on Jun. 19, 2010, to U.S.Provisional Application No. 61/356,589, filed Jun. 19, 2010 and to U.S.Provisional Application No. 61/469,100, filed Mar. 30, 2011 the entirecontents of which are incorporated herein by reference.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/356,589, and European Patent Application EP10166587, filedboth filed Jun. 19, 2010, and U.S. Provisional Patent Application Ser.No. 61/469,100 filed Mar. 30, 2011, all entitled “A system and methodfor determination of transpulmonary pressure in a patient connected to abreathing apparatus”, which are hereby incorporated herein by referencein their entirety for all purposes.

BACKGROUND OF THE INVENTION

Patients with acute respiratory failure in need for ventilator treatmentin intensive care units show highly varying pathophysiologic conditionsof the respiratory system. With regard to the heterogeneity of acutelung injury (ALI) and the more severe acute respiratory distresssyndrome (ARDS), the percentage of potentially recruitable lung, i.e.lung tissue that was collapsed but can be opened by a high pressureinflation is up to approximately 60%. One important reason for theheterogeneity is whether the patient has ARDS of pulmonary orextrapulmonary origin, i.e. whether it is the lungs per se or the chestwall and the diaphragm that are mainly affected. In most cases ofrespiratory failure, both the mechanical conditions of the lung, thestiffness (elastance=E) of the lungs (EI) and the stiffness of thecontaining wall, (Ec), chest wall and diaphragm, play an important role.

During ventilator treatment the mechanical properties of the totalrespiratory system was hitherto determined by the combined effect ofstiffness of the lungs and the stiffness of the chest wall/diaphragmworking in series. The lung is a compliant unit within another compliantunit, namely the chest wall and the diaphragm. For optimal ventilatortreatment, where risks and benefits of the treatment are balanced,knowledge of the stiffness of the chest wall in relation to thestiffness of the lung is of outmost importance.

For instance, the risk of inducing damage to the sensitive lung tissueby the ventilator treatment is increasing when the lung is very stiffand the chest wall/diaphragm is very soft, where most of the airwaypressure generated by the ventilator during inspiration acts solely onthe lung, i.e. a high transpulmonary pressure is present. Very little ofthe pressure applied by the ventilator to the patient is transmitted tothe surrounding chest wall and diaphragm.

On the other hand, in a case where the stiffness of the chest wall andespecially the diaphragm is increased, e.g. by abdominal inflammation,with resulting high sub-diaphragmatic pressures, the lung will belimited in its expansion by the stiffness of the chest wall anddiaphragm, and the transpulmonary pressure will be low. The risk ofventilator induced lung injury will be reduced. This was shown by Talmoret al, in a randomised study on oesophageal pressure guided mechanicalventilation in ARDS patients (Talmor et al NEJM 2008; 359(20):2095-2104).

As measurement of the transpulmonary pressure is difficult, ameasurement of the oesophageal pressure is used as a surrogate ofpleural pressure instead of measuring pleural pressure directly. Theoesophageal pressure is used as an indirect measure of how much airwaypressure is transferred through the lung to the chest wall and diaphragmduring assisted controlled ventilation. This makes it possible to givean estimate of the stiffness of the chest wall/diaphragm based on theoesophageal pressure.

The combined stiffness of the lungs and chest wall/diaphragm, totalrespiratory system stiffness (Etot), is the sum of the lung stiffnessand the chest wall/diaphragm stiffness. The stiffness of the lung maythus indirectly determined by subtraction of Ec from Etot. Thecalculation of chest wall and lung compliance is based on the tidaldifference in end-expiratory and end inspiratory oesophageal and airwaypressures (ΔPoes, ΔPaw).

However, there are practical difficulties of performing the oesophagealpressure measurement. Oesophageal pressure is measured by means ofcatheter like elongate pressure monitoring devices, such as disclosed inU.S. Pat. No. 4,214,593. The device comprises a nasogastric tubeprovided with an oesophageal balloon cuff.

The correct placement of the oesophageal balloon catheter in theoesophagus, especially in patients who already have a stomach tubeinserted through the oesophagus, has shown to be very difficult. It canbe compared with forwarding a soft spaghetti through a branched tubingstructure without vision during this action.

Moreover, the performance of the oesophageal balloon as a transmitter ofoesophageal pressure is influenced by how much it is preinflated and howmuch mediastinal weight, i.e. weight of the heart is superimposed on theballoon. Also, the reliability of the measurements has been questionedas oesophageal pressure is a substitute measure of pleural pressures,which are different in different places, due to gravitational forces andits proximity to the diaphragm, where abdominal pressure anddiaphragmatic stiffness have a greater impact.

In addition, an oesophagal balloon measurement provides a pressuremeasurement only for the horizontal plane in which the measurement isdone. Depending on the positioning in the patient thus differentmeasurement values will be obtained e.g. due to gravitational forcesacting on the patient body and in particular the lung, directly orindirectly via the weight if other organs in the thorax of the patient.There is a need of providing a measure representative of alltranspulmonary pressures irrespective of the position thereof, avoidingthe influence of factors such as gravitational forces acting on thepatient body.

Thus, besides the costs for the catheters and their use, the practicalpositioning difficulties and doubtful reliability of measurement valuesobtained have resulted in a very limited clinical use of suchoesophageal balloon catheter.

Another important issue is that measuring pleural pressure directly inthe pleural cavity surrounding the lungs is practically not possible asthe pleural space usually is very small and a risk of puncturing thelungs is impending but should be avoided by any means. It is highlyhazardous to measure the pleural pressure due to the risk of puncturingthe lung. Therefore, it has been attempted to use oesophagal pressure asa surrogate as described above.

Hence, there is a need for a new or alternative way of measuring ordetermining transpulmonary pressure in a patient connected to abreathing apparatus.

European Patent publication EP1295620 discloses a breathing apparatusfor use in the examination of pulmonary mechanics of a respiratorysystem.

TALMOR DANIEL ET AL: “Mechanical Ventilation Guided by EsophagealPressure in Acute Lung Injury”, NEW ENGLAND JOURNAL OF MEDICINE vol.359, no. 20, November 2008 (2008-11), pages 2095-2104, discloses a studyconcerning randomly assigned patients with acute lung injury or ARDS toundergo mechanical ventilation with PEEP adjusted according tomeasurements of esophageal pressure (the esophageal-pressure-guidedgroup) or according to the Acute Respiratory Distress Syndrome Networkstandard-of-care recommendations.

International PCT publication 2007/082384 discloses a method fordetermining dynamically respiratory feature in spontaneously breathingpatients receiving mechanical ventilatory assist.

An object of the present invention may be regarded as directdetermination of transpulmonary pressure without the use of oesophagealpressure measurements.

An improved or alternative system, computer program and/or method fordetermination of transpulmonary pressure without the use of indirectmeasures, such as oesophageal pressure measurements would beadvantageous. Moreover, it would be advantageous and to provide such asystem, computer program and/or method allowing for increasedflexibility when using existing breathing apparatuses,cost-effectiveness by avoiding purchase and use of additional equipmentneeded for the transpulmonary pressure determination, and userfriendliness thereof would be advantageous. It would also beadvantageous if such a measurement or determination provided a meanvalue for the transpulmonary pressure, i.e. a measure representative ofall transpulmonary pressures irrespective of the position thereof, e.g.due to gravitational forces acting on the patient body.

SUMMARY OF THE INVENTION

Accordingly, embodiments of the present invention preferably seek tomitigate, alleviate or eliminate one or more deficiencies, disadvantagesor issues in the art, such as the above-identified, singly or in anycombination by providing a breathing apparatus, computer program, andmethod according to the appended patent claims.

According to an aspect of the invention, a breathing apparatus isprovided having an inspiratory pressure sensor and flow sensor, anexpiratory pressure sensor and flow sensor, inspiratory valve, anexpiratory valve, and a control unit that is adapted to determine atranspulmonary pressure in a patient when connected to the breathingapparatus. The control unit is operable to a) set the breathingapparatus in a first mode of operation for ventilating the patient witha first Positive End Expiratory Pressure (PEEP) level; b) set thebreathing apparatus in a second mode of operation for ventilating thepatient with a second PEEP level starting from the first PEEP level,wherein the second PEEP level is based on a target PEEP level differentfrom the first PEEP level; c) determine a change in end-expiratory lungvolume (ΔEELV) from a difference of end-expiratory lung volume (EELV)present at the first PEEP level and the second PEEP level; and determinethe transpulmonary pressure (Ptp) based on the change in end-expiratorylung volume (ΔEELV) and a difference between the first PEEP level andthe second PEEP level (ΔPEEP).

According to a further aspect of the invention, a computer-readablemedium is provided having embodied thereon a computer program forprocessing by a computer. The computer program comprises a plurality ofcode segments for determining a transpulmonary pressure (Ptp) in apatient connected to a breathing apparatus. The code segments comprise afirst code segment for establishing a first Positive End ExpiratoryPressure (PEEP) level; a second code segment for changing a target PEEPlevel from the first PEEP level to a second PEEP level, different fromthe first PEEP level, and a third code segment for establishing thesecond PEEP level starting from the first PEEP level; a fourth codesegment for determining a change in end-expiratory lung volume (ΔEELV)from a difference of end-expiratory lung volume (EELV) present at thefirst PEEP level and the second PEEP level; and a fifth code segment fordetermining the transpulmonary pressure (Ptp) based on the change inend-expiratory lung volume (ΔEELV) and a difference between the firstPEEP level and the second PEEP level (ΔPEEP).

According to another aspect of the invention, a method of internally ina breathing apparatus is provided for determining a transpulmonarypressure (Ptp) in a patient connected to a breathing apparatus. Themethod comprises establishing a first Positive End Expiratory Pressure(PEEP) level; changing a target PEEP level from the first PEEP level toa second PEEP level, different from the first PEEP level, andestablishing the second PEEP level starting from the first PEEP level;determining a change in end-expiratory lung volume (ΔEELV) from adifference of end-expiratory lung volume (EELV) present at the firstPEEP level and the second PEEP level; and determining the transpulmonarypressure (Ptp) based on the change in end-expiratory lung volume (ΔEELV)and a difference between the first PEEP level and the second PEEP level(ΔPEEP).

The above computer program is preferably provided for enabling carryingout of the above method.

Further embodiments of the invention are defined in the dependentclaims, wherein features for the second and subsequent aspects of theinvention are as for the first aspect mutatis mutandis.

Embodiments of the invention avoid the use of indirect measurements oftranspulmonary pressure, such as based on oesophagal pressuremeasurements.

Embodiments of the invention also provide for a user friendly way ofdetermining transpulmonary pressure.

Embodiments of the invention may be implemented with existing breathingapparatuses without adding additional sensor units to the apparatus.

Embodiments of the invention provide for a measure of the transpulmonarypressure without measuring the pleural pressure.

Embodiments of the invention provide for patient safe and non-hazardousway of determining the transpulmonary pressure.

Embodiments of the invention provide for automated determination oftranspulmonary pressure.

Embodiments of the invention provide for deflection points at non-linearcompliances. A lower inflection point and/or an upper deflection pointmay be determined.

In embodiments the transpulmonary pressure is determined during assistedand/or controlled ventilation of a patient. The patient is notspontaneously breathing.

Some embodiments provide for determination of the transpulmonarypressure in a system and method when the patient is connected to thebreathing apparatus non-invasively, e.g. via breathing tubing and a facemask. Leakage should be kept at a minimum or can be detected andsuitably compensated in volume and pressure measurements in ways knownto use by the skilled person when reading the present description.

Transpulmonary pressure determined by such embodiments may be used toadapt a ventilation strategy of the patient. Adaptation of ventilationstrategy may be made in an automated way, upon user selection and basedon the determined transpulmonary pressure. Thus, lung injury of thepatient may be effectively avoided.

The transpulmonary pressure (Ptp) can be defined as the pressure thatkeeps the lung, when inflated in a distended condition, stretchedagainst the inner of the chest wall and the diaphragm. Thetranspulmonary pressure (Ptp) is the difference between the pressure inthe trachea, also called lung pressure (PI), and the pleural pressure inthe pleura, located inside the chest wall and outside of the lung,(Pcw).

Transpulmonary pressure determined by embodiments is a mean value forthe transpulmonary pressure, denoted Ptp hereinafter is thus Ptp(mean).This is an advantageous measure representative of all transpulmonarypressures irrespective of the position thereof in relation to the lung.

In summary, ΔEELV/ΔPEEP provides a calculation value for CL. This isprovided for the pressure/volume range in which a PEEP step isperformed. A most advantageous measurement is based on spirometricdetermination of the ingoing calculation parameters. At small PEEP stepsand volumes, the value is at an optimum. Small PEEP steps are in thiscontext up to 3 cmH₂O ΔPEEP. A clinically preferable range is 2-3 cmH₂O.Small volumes include ΔEELV being in the range of total tidal volume at0 PEEP. In absolute measures this is for instance 6 ml/kg predicted bodyweight for adult patients, which is about 400 ml for a 70 kg adult. Thisprovides for the most accurate determination of PTP while providing alung protective strategy.

It should be emphasized that the term “comprises/comprising” when usedin this specification is taken to specify the presence of statedfeatures, integers, steps or components but does not preclude thepresence or addition of one or more other features, integers, steps,components or groups thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects, features and advantages of which embodiments ofthe invention are capable of will be apparent and elucidated from thefollowing description of embodiments of the present invention, referencebeing made to the accompanying drawings, in which

FIG. 1 is a schematic illustration of an embodiment of a breathingapparatus;

FIG. 2 is a flow chart of an embodiment of a method;

FIG. 3 is a schematic illustration of an embodiment of a computerprogram;

FIG. 4 is a graph illustrating a change in PEEP and resulting volumechanges over time;

FIGS. 5A to 5F are pressure/volume graphs illustrating various stages ofan embodiment of a method performed on a breathing apparatus;

FIG. 6 is a schematic pressure/volume graph of an example of a patientwith non-linear compliance conditions;

FIG. 7 is a pressure/volume graph of the total respiratory system andchest wall at different PEEP levels;

FIG. 8 is a graph 8 illustrating a breath-by-breath increase inend-expiratory lung volume (ΔEELV) during an animal trial forverification of the method;

FIG. 9 is a graph 9 illustrating a correlation between theend-expiratory volume increase after the first expiration afterincreasing PEEP;

FIG. 10 is a correlation plot 10;

FIG. 11 are shows graphs 11, 12 of Volume and driving pressure during aPEEP step;

FIG. 12 is a schematic illustration 13 of a lung model;

FIG. 13 are diagrams 14, 15 comparing a change in transpulmonarypressure; and

FIG. 14 is a number of graphs 16, 17, 18, 19 showing changes intranspulmonary pressure in different settings.

DESCRIPTION OF EMBODIMENTS

Specific embodiments of the invention will now be described withreference to the accompanying drawings. This invention may, however, beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein; rather, these embodiments areprovided so that this disclosure will be thorough and complete, and willfully convey the scope of the invention to those skilled in the art. Theterminology used in the detailed description of the embodimentsillustrated in the accompanying drawings is not intended to be limitingof the invention. In the drawings, like numbers refer to like elements.

The following description describes an embodiment applicable to abreathing apparatus and in particular to a respiratory ventilator in useconnected to sources of pressurized gas. However, it will be appreciatedthat the invention is not limited to this application but may be appliedto many other breathing apparatuses, including for example fan drivenbreathing apparatuses. The embodiment described is a breathing apparatusin form of an intensive care respiratory ventilator. However, otherembodiments may comprise anaesthetic vaporizers, breathing circles, etc.connected to the breathing apparatus without deviating from theinvention. The invention is suited for all groups of patients, includingadult/paediatric patients or neonatal patients.

FIG. 1 is a schematic illustration of an embodiment of a breathingapparatus 1. In the embodiment a first source of pressurized gas 101,such as for air, and optionally further sources of pressurized gas 102,such as for oxygen and/or nitrous oxide, are arranged for providinginput gas to the breathing apparatus 1, usually to a housing 100. Asuitable mixture of gas is by means of one or more inspiratory gasvalves 110 controllably delivered to a patient 125 via an inspiratorybranch 116.

The inspiratory branch 116 comprises suitable tubing for conveying thegas mixture via a Y-piece 120 and a patient connection 121, such as aface mask, laryngeal mask, a tracheal cannula, or an endotracheal tube,to the patient 125 during an inspiratory phase. Inspiratory pressure ismeasured by means of a pressure transducer 113, e.g. at an inspiratorysampling point 111. Inspiratory flow towards the patient is measured bymeans of an inspiratory flow transducer 112.

An expiratory branch 126 comprises suitable tubing for conveying the gasfrom the Y-piece 120. The gas in the expiratory branch may compriseexhaled gas from the patient 125 during an expiratory phase, and/or abias flow from the inspiratory branch 116 passing the Y-piece 120directly without entering the patient 125. An expiratory valve 130controls the gas flow in the expiratory branch. During inspiration it isusually closed. Expiratory pressure is measured by means of a pressuretransducer 131, e.g. at an expiratory sampling point 131. Expiratoryflow to the expiratory valve 130 is measured by means of an expiratoryflow transducer 132. Gas passing the expiratory valve 140 is conveyedfurther to the surrounding environment or an evacuation system 141 viaan exhaust 140.

A control unit 105 provides for inspiratory breathing patterns to thepatient 125 during the inspiratory phase and expiratory control ofrelease of patient gas from the patient during the expiratory phase. Thecontrol unit is provided with signals from the inspiratory andexpiratory pressure and flow meters via lines 114, 115, 134, and 135,respectively.

The control unit 105 is adapted to determine a transpulmonary pressurePtp in a patient 125 connected to the breathing apparatus 1. The controlunit 105 is adapted to control the breathing apparatus suitably bycontrolling the inspiratory valve 110 and the expiratory valve 130.Feedback and measurements of inspiratory flow and pressure, as well asexpiratory flow and pressure are provided by the pressure transducers113, 133 and flow transducers 112, 132, respectively. Measurement valuesare collected and stored in a memory circuit (not shown) for access bythe control unit 105. Ptp is then calculated as described in more detailbelow. The obtained Ptp value may be used for adapting a continuedventilation strategy of the patient 125.

Thus controlled, the breathing apparatus 1 establishes an initial, firstPositive End Expiratory Pressure (PEEP) level. The first PEEP level maybe at ambient pressure, i.e. “0” relative to ambient pressure, or apositive pressure above ambient pressure. This first PEEP pressure isthe starting PEEP pressure for the manoeuvre now initiated to providemeasurement values for determining the Ptp.

A target PEEP level is changed from the first PEEP level to a secondPEEP level, which is different from the first PEEP level. Based on thistarget PEEP level, subsequent inspiratory and expiratory phases areadjusted to establish the second PEEP level starting from the first PEEPlevel. This transition is elucidated in more detail below with referenceto FIGS. 4, 5A-5F, and FIG. 6.

A change in end-expiratory lung volume ΔEELV is determined from adifference of end-expiratory lung volume (EELV) present at the firstPEEP level and the second PEEP level.

The transpulmonary pressure Ptp is determined based on the change inend-expiratory lung volume ΔEELV and a difference between the first PEEPlevel and the second PEEP level, ΔPEEP. At every PEEP level, anend-expiratory pressure equilibrium is present, which means that ΔPEEPis equal to ΔPtp, which implies that CL is ΔEELV divided by ΔPEEP. Thisdetermination is elucidated in more detail below.

Hence, Ptp is determined without the need for and oesophageal pressuremeasurement, or another sensor to be inserted into the patient thoraxfor indirect measurement thereof. Ptp is determined solely fromtransducers commonly present in a breathing apparatus. Measurementvalues thereof at determined stages of the aforementioned PEEP levelchange manoeuvre are processed and the value for Ptp is provided forfurther processing.

Alternatively to an integrated control unit 105 for both controlling theventilatory modes of the breathing apparatus 1 and the transpulmonarypressure determination, several control units may be provided, eachhaving a dedicated specific task, and which are suitably operativelyconnected.

A further example for application of the invention is illustrated inFIG. 2 in a flow chart of a method 2. The method 2 is a method ofdetermining a transpulmonary pressure Ptp in a patient connected to abreathing apparatus. The method comprises a number of steps. Initially,a first Positive End Expiratory Pressure (PEEP) level is determined asan existing PEEP level, or it is established in a step 23 to a desiredfirst PEEP level. The target PEEP level is then changed in a step 24from the first PEEP level to a second PEEP level, which is differentfrom the first PEEP level. Based on this target PEEP level, the secondPEEP level is established in a step 25 starting from the first PEEPlevel.

A change in end-expiratory lung volume ΔEELV is calculated in step 26from a difference of end-expiratory lung volume EELV present at thefirst PEEP level and the second PEEP level. The transpulmonary pressureΔPtp is then calculated in step 27 based on the change in end-expiratorylung volume ΔEELV and a difference between the first PEEP level and thesecond PEEP level ΔPEEP.

In another embodiment of the invention according to FIG. 3 a computerprogram 3 is illustrated stored on a computer readable medium 30 forexecuting by a processing device, such as the control unit 105. Thecomputer program comprises a plurality of code segments for determininga transpulmonary pressure (Ptp) in a patient connected to a breathingapparatus. The code segments comprise a first code segment 33 forestablishing a first Positive End Expiratory Pressure (PEEP) level; asecond code segment 34 for changing a target PEEP level from the firstPEEP level to a second PEEP level, different from the first PEEP level,and a third code segment 35 for establishing the second PEEP levelstarting from the first PEEP level; a fourth code segment 36 fordetermining a change in end-expiratory lung volume (ΔEELV) from adifference of end-expiratory lung volume (EELV) present at the firstPEEP level and the second PEEP level; and a fifth code segment 37 fordetermining the transpulmonary pressure (Ptp) based on the change inend-expiratory lung volume (ΔEELV) and a difference between the firstPEEP level and the second PEEP level (ΔPEEP).

The afore mentioned PEEP transition manoeuvre is now described in moredetail. The manoeuvre is described as a method. It is understood thatthe method may be implemented by the afore described breathing apparatus1 and the control unit 105 thereof, and/or a computer program.

A method of direct measurement of transpulmonary pressure is nowdescribed based on the assumption that the magnitude of theend-expiratory volume change following an end-expiratory pressure (PEEP)change is determined by the magnitude of the PEEP change and thecompliance of the lung, i.e. the transpulmonary pressure Ptp changeduring a PEEP change equals the PEEP change.

A stepwise change in end-expiratory pressure (ΔPEEP) level results in achange in end-expiratory lung volume ΔEELV.

In this context the preferential method is to use a spirometricdetermination of the ΔEELV by measuring the cumulative difference ininspiratory and expiratory tidal volumes between the first and thesecond PEEP level, i.e. from a first PEEP level of equal inspiratory andexpiratory volume until a second PEEP level equilibrium of inspiratoryand expiratory tidal volumes are reached. This is implemented by usingmeasurement signals from the inspiratory flow transducer 112 and theexpiratory flow transducer of the breathing apparatus 1.

FIG. 4 is a graph 4 illustrating an example of such a change in PEEP andresulting volume changes over time. In the illustrated example, thesecond PEEP level is lower than the first PEEP level. The schematicgraph 4 shows inspiratory (continuous line) and expiratory (dotted line)tidal volume measurements 101 over time t before. Curve segments a-f arereference signs for expiratory flow segments of expiratory phases ofsubsequent breathing cycles. An expiratory phase a is shown prior to thePEEP change. Expiratory phases after a release of PEEP (marked at thePEEP arrow in the figure) are shown at curve segments b, c, d, e and fduring assisted and/or controlled mechanical ventilation of thebreathing apparatus 1, here volume controlled ventilation.

The sum of the increase in expiratory volume (b−a+c−a+d−a+e−a+f−a) afterthe PEEP release until expiratory volume is stabilised at a newequilibrium is substantially the same as the expiratory volume beforethe PEEP release at (a). This sum is equal to the difference inend-expiratory lung volume EELV between the two PEEP levels.

An increase in EELV when increasing the PEEP from a first level to asecond, higher level, is calculated correspondingly.

Alternatively, or in addition, ΔEELV can be determined by a number ofother methods, such as CT scan before and after the PEEP change,FRC/EELV measurement by inert gas dilution technique before and afterthe PEEP change or by respiratory inductive plethysmography (RIP) orelectric impedance tomography (EIT), or any other suitable method.

-   -   The end-expiratory volume increase after the first breath after        the PEEP change is ΔPEEP×CTOT=×VI    -   wherein CTOT is the total compliance of the lung CL and        chestwall/diaphragma CCW, and the corresponding new        end-expiratory transpulmonary pressure is ΔPEEP×CTOT/CL=ΔP1    -   The end-expiratory volume increase after the second breath after        the PEEP change is (ΔPEEP−ΔP1)×CTOT=ΔV2 and the corresponding        end-expiratory mean transpulmonary pressure increase from ΔPI is        ΔV2/CL=ΔP2

During the following breaths, the change in lung volume and the changein end-expiratory pressure will follow in the same way and thebreath-by-breath volume and pressure changes will asymptoticallydecrease until the end-expiratory transpulmonary pressure has increasedwith the ΔPEEP.

An example of increasing the second level of PEEP is now discussed, withreference to FIG. 5A-5F, which are pressure/volume graphs illustratingvarious stages of the course of lung filling following a step increasein PEEP.

In the example, the patient has a CTOT of 40, CCW of 95 and CL of 67ml/cmH₂O. The total respiratory system course is illustrated by line 50at CTOT in FIG. 5, the chest wall course is illustrated by line 51 atCCW in FIG. 5, and the lung course is illustrated by line 52 at CL inFIG. 5.

FIG. 5A: ventilation is shown with a tidal volume of 400 ml and anairway pressure of 10 cmH₂O and an end-expiratory (PEEP) pressure of 0cmH₂O. The tidal chest wall pressure variations (ΔPCW) is just above 4cmH₂O resulting in a tidal transpulmonary pressure difference (ΔPtp)just below 6 cmH₂O.FIG. 5B: The first inspiration after changing the PEEP level to from thefirst PEEP level of 0 cmH₂O to the second PEEP level of 6 cmH₂O in theventilator, inflates the lung with 6×40=240 ml (ΔPEEP×CTOT) andincreases the lung pressure with 3.6 cmH₂O as the change in lungpressure is the change in lung volume divided by the lung compliance,240/67=3.6. Transpulmonary pressure increases at the same level as thelung pressure.FIG. 5C: The second inspiration inflates the lung with (6−3.6)×40=96 ml(remaining transpulmonary pressure to the next PEEP level equilibrium).The transpulmonary pressure will increase with 96/67=1.4 cmH₂O.FIG. 5D: The following breaths will continue to expand the lung until anew equilibrium is reached, i.e., until as much volume has been added tothe lung as determined by the compliance of the lung (67 ml/cmH₂O) andmagnitude of the PEEP increase (6 cmH₂O), in this case 400 ml.FIG. 5E: The first breath is shown after the volume/pressure equilibriumis reached at the new PEEP level of 6 cmH₂O. The total transpulmonarydifference at that PEEP level is the ΔPtp+PEEP over atmosphericpressure.FIG. 5F: The tidal ventilation at new lung volume level is presented,showing that the ratio between the difference in lung volume between thesecond and first lung volume and the difference in end-expiratorypressure between the second and first PEEP levels are ΔEELV/ΔPEEP whichcorresponds to the lung compliance, CL.The lung compliance CL is thus determined as ΔEELV/ΔPEEP.The total respiratory system driving pressure (ΔPaw) during mechanicalventilation is the difference between the airway pressure Paw during anend-inspiratory pause and an end-expiratory pausePaw−PEEP=ΔPaw  (1)The transpulmonary pressure difference (ΔPtp) between end of inspirationand end of expiration is the difference between the total respiratorysystem driving pressure (ΔPaw) and the chest wall pressure difference(ΔPcw) between end of inspiration and end of expiration.ΔPtp=ΔPaw−ΔPcw  (2)Total respiratory system compliance (CTOT) is the ratio of the tidalvolume VT to the total respiratory system driving pressure, namely theabove airway pressure difference ΔPaw:CTOT=VT/ΔPaw  (3)

The chest wall compliance (CCW) is the ratio of the tidal volume VT tothe plural/chest wall pressure difference ΔPcw:CCW=VT/ΔPcw  (4)The lung compliance (CL) is the ratio of the tidal volume VT to thetranspulmonary pressure differenceCL=VT/ΔPtp  (5)Stiffness, elastance (E) is the reciprocal of compliance andETOT=1/CTOT  (6)ECW=1/CCW  (7)EL=1/CL  (8)The lung elastance is the difference between the total respiratorysystem elastance and the chest wall elastanceEL=ETOT−ECW  (9)During tidal breathing, at a stable PEEP level, the lung elastance orcompliance cannot be determined without measuring the oesophagealpressure and then only indirectly calculated as the difference betweentotal respiratory system stiffness and chest wall/diaphragmaticstiffness.The Transpulmonary PressureA CTOT at the first PEEP level, which is equal to the CTOT of the secondPEEP level indicates that lung compliance is linear over the existingpressure range and the transpulmonary pressure can be calculated asΔPTP=ΔPaw×EL/ETOT  (10)Normally, the mechanical properties of the lung especially, but also thechest wall and diaphragm may change between two PEEP-levels as indicatedby a change in CTOT between the first and the second PEEP level. Whensuch a change is detected in CTOT between the first and the second PEEPlevel, inflection and deflection points may be determined or calculatedas described below.In a particular example, at certain tidal volumes, the transpulmonarypressure difference between two PEEP levels may be calculated asΔPTP=(ΔPaw1+ΔPaw2)/2×EI/ETOT  (11)Where ΔPaw1 is the inspiratory plateau pressure minus the end-expiratorypressure at the first PEEP level and ΔPaw2 is the inspiratory plateaupressure minus the end-expiratory pressure at the second PEEP level.Thus, the sum of the breath-by-breath volume increase following a stepchange in PEEP is the total lung volume change caused by an increase intranspulmonary pressure equal to the PEEP change, and lung compliance isCL=ΔEELV/ΔPEEP  (12)ΔPEEP is directly determined from measurements of the expiratorypressure transducer 133 at the first and second PEEP level. ΔEELV isalso determinable from spirometric measurements as described above,preferably by spirometry based on measurements of the breathingapparatus' flow transducers. Having thus determined CL from equation(12), ΔPTP is determined from equation (10). ΔPaw is advantageously inembodiments determined from measurements of the breathing apparatus,namely the inspiratory pressure transducer 113. ETOT is also determinedfrom measurements of the breathing apparatus, see equations (3) and (6),namely the inspiratory flow transducer 112 and the inspiratory pressuretransducer 113. Thus ΔPTP is determined based on these calculationswithout the need of measuring oesophagal pressure. Determining CL, suchas by equation 12, and thus ΔPTP has hitherto not been possible in suchan advantageous, convenient, patient safe and cost-effective way.Identification of Lower and Upper Inflection Points of Non-Linear P/VCurvesAs mentioned above, if CTOT at the PEEP level after changing PEEP haschanged from the CTOT at the first PEEP level before the change, thisindicates that either the lung and/or the chest wall compliance isnon-linear. A more precise identification of the level of change ofcompliance, a lower inflection point, where the second PEEP level CTOThas increased, may be performed by making smaller PEEP level changesand/or by reducing the tidal volume. An upper deflection point, wherethe second CTOT has decreased compared to the first PEEP level can beidentified more precisely in the same way. Combining small PEEP-stepsand/or small tidal volumes with equation 11, makes it possible toidentify the pressure-volume curve for the lung over the total lungcapacity.In an embodiment, when CTOT changes between PEEP levels, i.e. whennon-linear conditions are present, transpulmonary pressure at the firstPEEP level (Vt_(PEEP1)) is identified by a procedure where a stepwiseincrease in PEEP is performed until the sum of the stepwise obtainedΔEELV (ΣΔEELV) is equal or close to the tidal volume at the first PEEPlevel (Vt_(PEEP1)):ΣΔEELV=Vt_(PEEP1)The PEEP level where this ΣΔEELV is obtained is denominated lungcompliance PEEP (PEEP_(CL)) Lung compliance for the tidal volume at thefirst PEEP CLVt_(PEEP1) is calculated asCLVt_(PEEP1)=ΣΔEELV/(PEEP_(CL)−PEEP₁)and the transpulmonary pressure of the tidal volume of the first levelPEEP is calculated asΔPTPVt_(PEEP1)=ΔPaw×ELVt_(PEEP11)/ETOTVt_(PEEP1)  (13)At tidal ventilation at the highest PEEP level (PEEP_(PEAK)), that isdeemed possible to use for patient safety reasons, such as limited toavoid baro- and volotrauma, the CL above this PEEP level (CL_(PEAK))cannot be measured as such. However, the difference in end-inspiratorylung volume (ΔEILV) can be estimated based on the assumption that CTOTat the second highest PEEP level (CTOT _(SH)) is related to the ΔEELVmeasured between the second highest and the highest PEEP level as CTOTat tidal ventilation at the highest PEEP level (CTOT PEAK) relates tothe end-inspiratory volume difference:CTOT _(SH)/ΔEELV=CTOT _(PEAK)/ΔEILVwhich rearranged givesΔEILV=CTOT _(PEAK)×ΔEELV/CTOT _(SH)  (14)and CL _(PEAK) can be calculated either by regarding the difference inΔPaw at PEEP_(PEAK) and PEEP_(SH) (ΔPaw_(PEAK-SH)) as a correspondingchange in transpulmonary pressure as obtained by a PEEP changeCL _(PEAK)=ΔEILV/ΔPaw_(PEAK-SH)  (15)or asCL _(PEAK)=ΔEILV/ΔPEEP_(PEAK-SH)where the largest pressure difference of ΔPaw_(PEAK-SH) orΔPEEP_(PEAK-SH) is selected for the calculation. The transpulmonarypressure at the highest PEEP level PTP _(PEAK) is then calculated byequation (10) asPTP _(PEAK)=ΔPaw_(PEAK)×EL _(PEAK)/ETOT _(PEAK)  (16)

FIG. 6 is a schematic pressure/volume graph of an example of a patientwith non-linear compliance conditions and are given as illustrativeexamples when implementing the above described system and method.

FIG. 6 is a schematic graph 7 of a patient with linear chest-wallcompliance (here 100 ml/cmH₂O) and a non-linear lung compliance, with aCL of 26 ml/cmH₂O below 5 cmH₂O, the lower inflection point 70 and a CLof 66 ml/cmH₂O between 5 and 15 cmH₂O, and a CL of 26 ml/cmH₂O above 15cmH₂O, the upper inflection point 71. Corresponding total compliancevalues are 20, 40 and 20 ml/cmH₂O in the three ranges, respectively.For correct determination of the transpulmonary pressure during thetidal volume at zero PEEP, the PEEP should be increased until ΔEELV isequal to the tidal volume (450 ml), which in this case would have beenachieved increasing PEEP to just above 9 cmH₂O. At the highest safe PEEPlevel the transpulmonary pressure can be calculated by determination ofthe end-inspiratory lung volume difference between the tidal volume at 7and 12 cmH₂O (ΔEILV), which is calculated according to equation (14) asΔEILV=26×340/40=221 ml(=CTOT×ΔEELV/CTOT)The change in transpulmonary pressure causing this volume change is thedifference in ΔPaw of the tidal volume at 12 and 7 cmH₂O inPEEP=17.5−11.4=6.1 cmH₂O.The CL of the tidal volume at the highest PEEP level is calculatedaccording to equation (15):221/6.1=36 ml/cmH₂O(CL=ΔEILV/ΔPEEP)The transpulmonary pressure of that tidal volume is calculated accordingto equation (16):17.5 cmH₂O×26/36=12.6 cmH₂O(Ptp=ΔPaw_(PEEP12)×EL _(PEEP12)/ETOT_(PEEP12))Indirect Determination of Chest Wall/Diaphragmatic Elastance (ECW)When both the total respiratory system stiffness, Etot, and the lungstiffness, EI, have been determined by the above described method, thestiffness of the chest wall/diaphragm can be determined indirectly asECW=ETOT−EL  (17)This calculation is sensitive to the conditions under which the ETOT hasbeen obtained, as an underestimation of ETOT leads to an overestimationof EL. To avoid this, ETOT may be measured under true static conditions,i.e. both the end-inspiratory and the end-expiratory pressure should bemeasured after an end-inspiratory/end-expiratory pause of substantialduration (>4 seconds) to release visco-elastic forces and identify anintrinsic PEEP.

FIG. 7 is a pressure/volume graph 6 of the total respiratory system(CTOT) and chest wall (CCW) at different PEEP levels. The schematicgraph 6 of tidal P/V curves of the total respiratory system and chestwall is shown at 0, 10, 20 and 30 cmH₂O PEEP. As the P/V-curve of thelung consist of the difference of P/V curves of the total respiratorysystem and chest wall, the start of tidal P/V curves are positionedalong the P/V curve of the lung. Lung compliance is determined asΔEELV/ΔPEEP, in this case 750/10=75.

A method of online adjusting a PEEP level based on a transpulmonarypressure (Ptp) determined according to the above method compriseslimiting PEEP to a lower level when lower transpulmonary pressures toprotect the lung from injury.

In unhealthy lungs, some air sacs of the lung may collapse. In thosecollapsed sacs, gas cannot enter or leave them, thus preventing gasexchange through the collapsed air sacs. The ventilator 1 may supply ahigher concentration of oxygen in order to provide proper bloodoxygenation. In addition, or alternatively, the ventilator 1 may supplyan adjusted positive end-expiratory pressure (PEEP) to maintain airwaysopen, based on the aforementioned determined transpulmonary pressure.For instance, by increasing the transpulmonary pressure, collapsed airsacs will start to recruit. When the collapsed air sacs start to openup, they are again available for alveolar gas exchange and the pressureat which the recruitment happens is called the critical openingpressure. The PEEP level is selected to prevent collapse duringexpiration by identifying a lower inflection point as described above.It is avoided to increase the transpulmonary pressure such thatoverinflation is avoided. Overinflation may be dangerous for the patientsince it may cause undesired lesions in the lung tissues.

A desired transpulmonary pressure may be adjusted accordingly andcontrolled by repeating the afore described PEEP step manoeuvre.

Setting said breathing apparatus in the second mode of operation (PEEPstep) may be selectable from a user interface of said breathingapparatus. The control unit may be adapted to automatically determinesaid transpulmonary pressure upon said user initiation. Further, theautomatic determination may be made during assisted and/or controlledventilation of said patient by said apparatus. This automaticdetermination may be made intermittently during the assisted and/orcontrolled ventilation. The manoeuver may be made at pre-defined timeintervals.

The number of breathing cycles in the second mode of operation beforebeing able to determine the transpulmonary pressure is at least one. Thecloser to an equilibrium the PEEP has adjusted itself to the desiredPEEP, the more precise the determined value is. Thus, a single breath inthe second mode of operation may be sufficient under certaincircumstances. Usually, the second mode of operation will be performedover a plurality of breathing cycles before the transpulmonary pressureis calculated or determined or a value therefore provided.

Animal Studies for Verification

Animal studies were performed to demonstrate the feasibility, effect andefficiency of transpulmonary pressure determination as described herein.The effects of a stepwise increase in PEEP on lung volume and esophagealpressure were analyzed breath by breath. In addition to thedemonstration of the measurement principle, also the influence of lungand chest wall mechanics on lung inflation by PEEP were analyzed. Anexplanation of the physiological and anatomical relationship underlyingthe effect and efficiency of transpulmonary pressure determination isalso given below. The physiological background for the measurement hasbeen found to be the phenomenon that by cohesion between the visceraland parietal pleura, the lung is pulled out against its recoil to theinner volume of the thoracic cavity and the thoracic wall is pulled into a balancing pressure/volume level. At atmospheric end-expiratorypressure, this results in a positive transpulmonary pressure in spite ofzero airway pressure. As described above, lung compliance is bedetermined as DEELV/DPEEP and transpulmonary pressure calculated as theairway pressure times the total respiratory system compliance divided bythe lung compliance. This method is below called “Lung Barometry”.

The studies were performed on pigs which were anesthetized andsacrificed and experiments were performed ex vivo. Tracheal andesophageal pressures were measured and changes in end expiratory lungvolume determined by spirometry as the cumulative inspiratory-expiratorytidal volume difference. Studies were performed with differentPEEP-steps and body positions and with varying abdominal load.

The study was approved by the Committee for Ethical Review of AnimalExperiments in Gothenburg, Sweden, and performed in accordance withNational Institutes of Health guidelines. Fourteen pigs (28-33 kg) werestudied. For anesthesia, the animals were premedicated using 15 mg/kgketamine (Ketalar, Park-Davis, Sweden) and 0.3 mg/kg midazolam(Dormicum, Roche, Switzerland) intramuscularly. General anesthesia wasinduced with 6 mg/kg pentobarbital sodium (Apoteksbolaget, Sweden),followed by hourly infusions of 4 mg/kg and 25 μg/kg fentanyl (FentanylPharmalink, Pharmalink, Sweden). Muscle relaxation was achieved by 0.15mg/kg pancuronium (Pavulon, Organon, Sweden) as a bolus. The pigs wereintubated with an 8-mm endotracheal tube (ETT). Mechanical ventilationwas performed using a Servo 300 ventilator (Siemens-Elema, Sweden),volume-controlled mode (VCV), TV 10 ml/kg, and inspiratory oxygenfraction of 0.21.

Tracheal airway and esophageal pressure was measured via a pressure lineintroduced through the ETT, which was connected to a standard pressurereceptor for intravascular measurements (PVB Medizintechnik, Germany).Esophageal pressure was measured with a balloon catheter positioned atthe lower part of the esophagus. Correct positioning was verified by arib cage compression test according to Baydur A, Behrakis P K, Zin W A,Jaeger M, Milic-Emili J. A simple method for assessing the validity ofthe esophageal balloon technique. Am Rev Respir Dis. 1982 November;126(5):788-91. Ventilatory flow and volume were measured at the Y-piecewith a D-lite side stream spirometer connected to an AS/3 multi-modulemonitor (GE Healthcare, Helsinki, Finland).

For electric impedance tomography (EIT) an elastic belt with sixteenelectrodes was placed around the chest wall and connected to the EITdevice (Dräger, Germany). EIT data were generated by application ofelectrical currents of 5 mA, 50 kHz with measurements of voltagedifferences between neighboring electrode pairs in a sequential rotatingprocess, where a complete scan was sampled at 25 Hz. The scan slice hasan estimated thickness of 5-10 cm. The electrodes were positioned at alevel corresponding to the 5th intercostal space. This level was chosenin accordance with previous findings, where tidal amplitudes of theimpedance changes were least affected by increased PEEP. Globalelectrical impedance end-expiratory level was calibrated vs FRC measuredwith N₂ washin/washout technique. Tidal impedance changes werecalibrated by changing tidal volume in steps of 100-200 ml.

End-expiratory lung volume (EELV) was measured using a modifiedtechnique for nitrogen washout/washin according to Olegard C et al,“Estimation of functional residual capacity at the bedside usingstandard monitoring equipment: a modified nitrogen washout/washintechnique requiring a small change of the inspired oxygen fraction.”,Anesth Analg. 2005 July; 101(1):206-12.

End-expiratory lung volume increase (ΔEELV) following a PEEP step(ΔPEEP) was spirometrically determined by addition of theinspiratory-expiratory tidal volume difference of the breaths needed forestablishing the new PEEP level. This determination was done using theServo 300 spirometry. Also, the ΔEELV was determined using the change inend-expiratory impedance (ΔZ) following a PEEP step. The change inimpedance was converted to ml by using the mean value of the ΔZ/ml atthe first and second PEEP level.

The tidal variation in esophageal pressure (APES) was determined asPESEIP−PESEE, where PESEIP is the end-inspiratory esophageal plateaupressure and PESEE the end expiratory esophageal pressure. The tidaltranspulmonary pressure variation (APES) was calculated as theΔPAW−ΔPES. The tidal transpulmonary pressure variation (ΔPTP) wascalculated as the ΔPAW−ΔPES.

Total respiratory system compliance (CTOT) was calculated as theVT/ΔPAW, where VT is the tidal volume. Total respiratory systemelastance (ETOT) was calculated as 1/CTOT. Chest wall compliance (CCW)was calculated as VT/APES. Chest wall elastance (ECW) was calculated as1/CCW. Lung elastance (EL) was calculated as ETOT−ECW and lungcompliance as 1/EL.

The driving pressure related to the PEEP step induced inflation(ΔPAWΔPEEP) of the respiratory system was calculated as ΔEELV×ETOT. Theend-expiratory increase in esophageal pressure related to the PEEP stepinduced inflation (ΔPESΔPEEP) of the respiratory system was calculatedas ΔEELV×ECW. The end-expiratory increase in transpulmonary pressurerelated to the PEEP step induced inflation (ΔPTPΔPEEP) of therespiratory system was calculated as ΔEELV×ETOT−ΔEELV×ECW.

Predicted ΔEELV was calculated as ΔPEEP/EL, ΔPEEP/ECW and as ΔPEEP/ETOT.

Experimental Procedure

In Vivo

Ventilation was set to volume control mode, tidal volume 10-12 ml/kgbody weight, respiratory rate 10, inspiratory time 30%, end-inspiratorypause 10%. A step increase in PEEP from 0 cmH₂O to 12 cmH₂O wasperformed. After the expiratory tidal volume returned to the zero PEEPlevel, or after >80 seconds, PEEP was reduced in one step to zero cmH₂O.

As the main aim of this study was to study respiratory mechanics and notgas exchange, the animal was then sacrificed by an overdose ofpentobarbital. This eliminated the cardiac related pressure variationsin the pressure signal resulting in an ex vivo respiratory mechanicslung model.

Ex Vivo

The duration of the ex vivo experimental procedure was around 120minutes.

1. EIT calibration by changing tidal volume stepwise from baseline 250to 300, to 500 and to 700 ml.

2. Pig positioned horizontal supine.

2:1. Tidal volume calibration of EIT

2:2. PEEP up from 0 to 4 cmH₂O and back to 0 cmH₂O

2:3. PEEP up from 0 to 8 cmH₂O and back to 0 cmH₂O

2:4. PEEP up from 0 to 12 cmH₂O and back to 0 cmH₂O

3. Pig positioned horizontal supine.

3:1. Abdomen loaded with sandbags weighing 8 kg.

3:2 Tidal volume calibration of EIT

3:3. PEEP up from 0 to 4 cmH₂O and back to 0 cmH₂O

3:4. PEEP up from 0 to 8 cmH₂O and back to 0 cmH₂O

3:5. PEEP up from 0 to 12 cmH₂O and back to 0 cmH₂O

3:6 Weight removed

4. Pig positioned horizontal supine.

4:1. Operating table positioned reverse Trendelenburg with an angle of30°.

4:2. Tidal volume calibration of EIT

4:3. PEEP up from 0 to 4 cmH₂O and back to 0 cmH₂O

4:4. PEEP up from 0 to 8 cmH₂O and back to 0 cmH₂O

4:5. PEEP up from 0 to 12 cmH₂O and back to 0 cmH₂O

4:6. Operating table returned to horizontal position.

5. Tidal volume calibration of EIT

6. PEEP up from 0 to 12 cmH₂O and back to 0 cmH₂O

Results

Lung and chest wall mechanics for the 13 ex vivo pig experiments atbaseline in horizontal position are presented in Table 1.

Horizontal E_(TOT) E_(CW) E_(Lung) E_(L)/E_(TOT) P1 142.7 20.0 122.60.86 P2 43.9 6.6 37.3 0.85 P3 41.1 15.6 25.5 0.62 P4 53.3 16.3 37.0 0.69P5 46.6 23.7 22.9 0.49 P6 105.0 12.0 93.0 0.89 P7 65.7 14.4 51.3 0.78 P835.6 20.5 15.1 0.42 P9 81.0 15.4 65.6 0.81  P10 36.0 13.7 22.4 0.62  P1135.0 14.0 21.0 0.60  P12 73.2 18.7 54.5 0.74  P13 37.9 14.5 23.3 0.62Mean 57.7 16.1 41.5 0.68 ± SD 31.0 4.3 30.0 0.14

Table 1 (above). Baseline, horizontal position mechanics

Successive inflation of the lungs following a PEEP increase in ex vivopigs in horizontal position, see FIG. 8. In FIG. 8, the breath-by-breathincrease in end-expiratory lung volume (ΔEELV) following a change inPEEP is increased from 0 to ˜12 cmH₂O in a pig at zero PEEP, reverseTrendelenburg, with a total respiratory system elastance of 41.7cmH₂O/L, a chest wall compliance of 20.4 cmH₂O/L and a lung complianceof 20 cmH₂O/L and a tidal volume of 250 ml. Note, that the firstexpiration build-up of lung volume is equal to the tidal volume, 250 ml.In comparison the calculated first expiratory increase in lung volumeshould have been ΔPEEP/ETOT, i.e. 11/0.042=264 ml.

The increase in EELV after the first breath following the PEEP increasewas closely correlated to ΔPEEP/ETOT_(zeroPEEP), r²=0.90, whereETOT_(zero)PEEP is the total respiratory system elastance measured at 0cmH₂O PEEP prior to the PEEP step, see FIG. 9. FIG. 9 is a graphillustrating a correlation between the end-expiratory volume increaseafter the first expiration after increasing PEEP.

The correlation between the measured ΔEELV using spirometry and ΔEELVpredicted from the ΔPEEP/EL_(calVT) was r²=0.70, y=1.13x, whereEL_(calVT) is the lung elastance calculated from tidal changes in airwayand esophageal pressures obtained from the calibration breaths performedbefore the PEEP change at the tidal volume closest to the ΔEELV whichoccurred following the PEEP change, see FIG. 10. FIG. 10 is acorrelation plot of measured end-expiratory lung volume change usingspirometry and the end-expiratory lung volume change calculated fromlung elastance and the PEEP change (ΔPEEP/EL).

If prediction of ΔEELV following a PEEP step was performed from valuesof total elastance (ETOT), ΔPEEP/ETOT results in predicted values beingaround 0.73 times the spirometrically measured ΔEELV (r²=0.84, y=0.73×).Prediction of ΔEELV using chest wall elastance (ECW), i.e. ΔPEEP/ECWresults in predicted lung volume changes being around 2.3 times themeasured ΔEELV (r²=0.61, y=2.31x).

The Driving Pressure of a PEEP Induced Respiratory System Inflation

The driving pressure of a PEEP induced inflation of the respiratorysystem was calculated as ΔEELV×ETOT. This cumulative driving pressurecan be considered to be exerted during the preceding inspiration of eachbreath involved in establishing the new end-expiratory pressure-volumeequilibrium as shown in FIG. 11. FIG. 11 shows graphs of Volume anddriving pressure during a PEEP step of 12 cmH₂O in pig 8 Supine. TheUpper panel in FIG. 11 shows the spirometric tracing of lung volumeincrease breath by breath. In the lower panel of FIG. 11, the drivingpressure is indicated by thicker lined bars of the inspiratory airwaypressure increase correlating to the increase in lung volume for eachbreath.

Changes in Esophageal Pressure During a PEEP Step

Tidal variations in esophageal pressure (APES) before and after a PEEPstep did not change substantially and was 5.8±2.2 cmH₂O at zero PEEP and5.5±2.2 cmH₂O, 5.1±1.7 cmH₂O, and 5.1 ±1.6 cmH₂O at a PEEP of 4, 8 and12 cmH₂O respectively. The end-expiratory esophageal pressure (PESEE)increase was closely correlated to the first end-expiratory lung volumeincrease and the chest wall elastance, ΔEELV1×ECW (r²=0.80, y=0.87x).

After the first expiration, there was no further increase in PESEE inspite of a continuing increase in end-expiratory lung volume. Horizontalposition, ΔPEEP12 cmH₂O, ΔEELV 580 ml. The end-expiratory esophagealpressure did not increase after the first expiration in spite of acontinuing increase in lung volume.

Abdominal Loading

Applying a weight of 8 kg on the upper abdomen resulted in an increasein end-expiratory esophageal pressure (PESEE) from −1.8±2.1 cmH₂O to−1.22±3.0 cmH₂O. Abdominal loading resulted in an increase in both lungand chest wall elastance from 50.1±36.5 and 17.1±4.5 cmH₂O/L to65.3±33.8 and 29.2±8.9 cmH₂O/L respectively. The ratio of lung to totalrespiratory system elastance (EL/ETOT) was 0.78±0.14 before and0.70±0.14 after abdominal loading.

Following loading there was no change in the end-expiratory airwaypressure, but the end-expiratory esophageal pressure, which immediatelyincreased following the PEEP increase gradually returned the pre-loadinglevel during the experimental sequence.

Reverse Trendelenburg Effects

Tilting of the pig head up 30° resulted in a decrease in end-expiratoryesophageal pressure (PESEE) to −5.1±2.2 cmH₂O. Lung elastance decreasedfrom 50.1±36.5 to 44.5±23.1 cmH₂O/L. Chest wall elastance increased from17.1±4.5 to 19.9±4.0 cmH₂O/L. The ratio of lung to total respiratorysystem elastance (EL/ETOT) after tilting was 0.71±0.1.

Following reverse Trendelenburg positioning, there was no change in theend-expiratory airway pressure, but the end-expiratory esophagealpressure, which immediately decreased gradually returned the pre-tiltlevel during the experimental sequence.

Discussion

In this ex vivo study of respiratory mechanics it was shown that thelung volume increase, ΔEELV, caused by stepwise raising theend-expiratory pressure involves several breaths even when the resultingΔEELV is less than a tidal volume. The driving pressure needed toinflate the lung and push the chest wall out is exerted during theinspiratory phase of the breaths involved in establishing a newend-expiratory pressure-volume equilibrium and the driving pressure canbe calculated from the size of the volume change and the elastance ofthe total respiratory system as ΔEELV/ETOT. The end-expiratory pressureesophageal pressure did not further increase after the first expirationafter increasing PEEP even though the end-expiratory lung volumecontinued to increase and the end-expiratory esophageal pressure wasnegative or minimally positive even at 12 cmH₂O of PEEP. The chest wallP/V curves were successively left shifted when PEEP was increased. TheΔEELV following a PEEP increase seems to be predictable from the degreeof PEEP increase ΔPEEP and the lung elastance as ΔPEEP/EL.

Breath by Breath Build Up of End-Expiratory Pressure and Volume

The PEEP induced inflation of the respiratory system is signified by theforce necessary to inflate the lungs and to push the chest wall to itsnew end-expiratory pressure-volume equilibrium. This force, the drivingpressure, is exerted during the inspiration preceding each of thebreaths involved in the build-up of a new end-expiratory pressure andlung volume equilibrium. This is especially evident concerning the firstexpiration after increasing PEEP, where the volume is closely related toΔPEEP/ETOT.

The end-expiratory lung volume increase continues breath by breath, andeach breath has the driving pressure of the difference between theinspiratory and expiratory tidal volume, the tidal ΔEELV times theelastance of the lung and the chest wall. Thus, the driving pressureneeded to establish a new pressure-volume equilibrium is equal to thetotal change in end-expiratory lung volume times the total respiratorysystem elastance. The driving pressure of the PEEP step can be regardedas the airway pressure of an ordinary tidal inspiration with a volumeequal to the change in end-expiratory lung volume.

A PEEP increase results in a multi-breath, successively decreasingbuild-up of the end-expiratory lung volume. In the present study, wherevolume control ventilation was used, the inspiratory tidal volume isconstant from before the PEEP change until a new equilibrium is reached.The expiratory tidal volumes, in contrast, change during the course ofthe PEEP increase. The first expiratory tidal volume after the PEEPincrease is lower than the preceding inspiration and equals the ΔPEEPdivided by the total respiratory system elastance (ETOT). The followingexpirations will increase successively until the expiratory tidal volumeis equal to the inspiratory tidal volume and a new end-expiratorypressure-volume equilibrium is reached.

Stress Adaptation

No pre-study inflation was used and the stress adaptation was studiedduring ex-vivo ongoing ventilation without gas exchange. Thus, very timeconsuming adaptation over 15-30 minutes could be studied. The pronouncedplasticity of the respiratory system was shown especially after reverseTrendelenburg positioning and abdominal weight application (see FIG. 8)where the end-expiratory esophageal pressure decreases and increasesrespectively. During the course of the following experimental procedures(10-20 minutes) with tidal volume calibration and PEEP increase anddecrease, end-expiratory esophageal pressure slowly returned to thebaseline prior to that the animal was tilted or abdominal weight wasapplied.

Changes in Esophageal Pressure During PEEP Elevation

Absolute esophageal pressure measurements in supine position may bemisleading due to the effects of mediastinal tissue weight upon on theesophageal measurement balloon. As the esophageal pressure is asurrogate measurement of pleural pressure, the end-expiratory esophagealpressure trace at zero PEEP was transpositioned to −5 cmH₂O, which is acommonly reported mean pleural pressure. Even at 12 cmH₂O PEEP, thetranspositioned end-expiratory esophageal pressure remained negative.

An increase in PEEP only marginally changed the end-expiratoryesophageal pressure level and the absolute increase in esophagealpressure was limited to the first expiration after the PEEP increase.This is a surprising finding as the increase in lung volume andconsequently also in thoracic cavity volume continues for a number ofbreaths after the first expiration. This lack of further increase inend-expiratory esophageal pressure during ongoing increase inrespiratory system volume may be caused by the properties of thethoracic cavity enclosement in a wide sense, including the rib cage andits muscles, the diaphragm and the abdominal wall and the abdominalcontent, adapting to the volume expansion by merely yielding i.e. stressadaptation.

The abdomen can be regarded as a fluid filled container, with a volumeof around 10 liters which in the supine position has a ventro-dorsalheight of approximately 15 cm. The abdominal the “surface” area of theabdominal container is approximately 7 dm². Increasing theend-expiratory lung volume 0.5 l by increasing PEEP results in a surfacelevel lift of 0.7 cm and an end-expiratory esophageal pressure increasewith approximately 0.7 cmH₂O.

As abdominal wall stress adaption seems to result in a further increasein abdominal surface area, the end-expiratory esophageal pressureincrease may be even less. There was very little increase in endexpiratory esophageal pressure at zero and 3 cmH₂O of PEEP at 5 mmHg ofabdominal pressure and no further increase when the abdominal pressurewas increased to 10 mmHg. This pattern is even more evident at a PEEP of8 cmH₂O in the study, which resulted in a moderate end-expiratoryesophageal pressure increase when an abdominal pressure of 5 mmHg wasimplemented. The end-expiratory esophageal pressure did not furtherincrease when the abdominal pressure was increased to 10 mmHg, whichindicates that abdominal wall yields and abdominal pressure was nottransmitted to the thoracic cavity.

The Role of the Diaphragm

The PEEP induced end-expiratory lung volume expansion results in adisplacement of the diaphragm and the abdominal content in caudal andlateral direction with very little change of chest wall elastance. Inthe present study, the esophageal tidal pressure-volume variationsshowed that the chest wall P/V curve is successively left and parallelshifted with increasing PEEP steps and the P/V curve of each PEEP levelhave approximately the same slope, which is fully in accordance withstress adaptation of the abdominal wall. This is further supported bythe fact that the diaphragm muscle loses its basic end-expiratorytension, maintained during spontaneous breathing and converts to apassive structure during positive pressure ventilation. Theend-expiratory tension is determined by the diameter of the rib cage,the length of the diaphragm and the hydrostatic abdominal pressureduring controlled ventilation. During spontaneous breathing thediaphragmatic muscle tension, possibly especially the crural (dorsal)portion, prevents the abdominal content to push the dependent diaphragmin cranial direction even if the whole diaphragm is displaced in cranialdirection when changing position from standing to supine. This movementis in spontaneous breathing subjects largely equal in non-dependent anddependent regions.

When controlled ventilation is started, the end-expiratory tension ofthe diaphragm is lost, the diaphragm is moved cranially and theventro-dorsal diameter of the rib cage decreases as the diaphragm ispassively stretched by the force of the hydro-static pressure from theabdomen. The cranial movement of the diaphragm will be most pronouncedin the dorsal, dependent region, which is most exposed to thehydro-static pressure of the abdomen and end-expiratory lung volumedecreases predominately in the dependent lung regions.

The Role of the Rib Cage

The rib cage is the resilient framework of the thoracic cavity and thelever for action of the respiratory muscles, intercostal and diaphragm.At FRC, the rib cage wants to spring out to a resting position around700 ml above FRC. In contrast the lung at FRC wants to recoil to belowits residual volume, around 500 ml below FRC (Nunn's Applied respiratoryphysiology. 4th edition, chapter 3, page 48. Butterworth, Heinemann,1995). These two contra-directional forces results in a mean positivetranspulmonary pressure equal to the negative mean pleural pressure,usually around 5 cmH₂O. Even though there is no pressure gradientbetween the alveoli and the ambient room, the whole lung is open even atFRC. Thus, the lung is suspended within the thoracic cavity and if theend-expiratory lung volume is changed by an increase in end-expiratorypressure, the “FRC compliance” can be determined as ΔEELV/ΔPEEP. Thisimplicates that at any level of end-expiratory pressure above zero, theonly force that prevents the lung from recoiling is the end-expiratorypressure maintained by the ventilator. Further, this implies that therib cage acts as a frame preventing the chest wall and diaphragm fromleaning on, or squeezing the lung even at increased PEEP levels. Thespring out force of the rib cage can be estimated to be present up toend expiratory lung volumes of levels >4 liters as a PEEP instigatedincrease in end-expiratory lung volume will be distributed between therib cage and the diaphragm, which is pushed in caudal direction. If FRCis 2.5 l an increase of lung volume up to 4 liters will expand the ribcage with approximately 0.7 l and the rest of the volume will displacethe diaphragm. During controlled ventilation, the end-expiratory lungvolume is decreased by 0.5 l in a healthy supine person and much more inpatients with respiratory failure, which means that the PEEP can beincreased significantly without losing the “spring out force” of the ribcage. We found that the transpositioned end-expiratory esophagealpressure only in a few cases reached atmospheric level even at highPEEP. This further underlines that, at end of expiration, the lung issuspended by the spring out force of the rib cage and the only forcepreventing its recoil is the end-expiratory pressure of the ventilator.Thus, at end-expiration, the chest wall does not seem to exert apressure on the lung and only the end-expiratory airway pressure,maintained by the ventilator, prevents the recoil of the lung.

Passive expiration is not a single compartment, but a two compartmentphenomenon, with rapid initial flow and a slow final flow. The initialphase of expiration is passive by recoil of the stretched tissues, butat the later part, the expiration is slower, which may be explained bythe rib cage springing out or stopping at a higher volume during thelast part of expiration. The increase in rib cage diameter will lead toa passive stretching of the diaphragm, which will counteract the cranialmovement of the abdominal content. As a result, the expiratory flow isdecreasing during the end of expiration, and at static conditions atend-expiration the rib cage is in a spring out state and the diaphragmstretched, which will keep the pleural pressure negative even atincreased PEEP levels.

Relation Between Changes in End-Expiratory Pressure (ΔPEEP) and LungVolume (ΔEELV) During PEEP Elevation

It is well known that the increase in end-expiratory lung volumefollowing a PEEP increase cannot be predicted from the size of the PEEPstep and the total respiratory system compliance. Prediction of ΔEELVcalculated as the change in end-expiratory pressure divided by the totalrespiratory system elastance (ΔPEEP/ETOT) in this study resulted inpredicted volumes which were only around half of the spirometricallymeasured ΔEELV following a PEEP step. Prediction of the change inend-expiratory lung volume calculated as the change in end-expiratorypressure divided by the chest wall elastance (ΔPEEP/ECW) resulted inpredicted volumes twice the measured ΔEELV. Prediction of the change inend-expiratory lung volume calculated as the change in end-expiratorypressure divided by the lung wall elastance (ΔPEEP/EL) resulted inpredicted volume being fairly closed to measured ΔEELV, (r²=0.70), whichindicates that the end-expiratory transpulmonary pressure seems tocontinue to increase breath by breath also after the first expirationuntil a new end-expiratory pressure/volume equilibrium is reached, wherethe increase in end-expiratory transpulmonary pressure equals the changein end-expiratory airway pressure, ΔPEEP.

In summary, a PEEP step results in a marginal build-up of end-expiratoryesophageal pressure as the chest wall and abdomen accommodates changesin lung volume by stress adaptation, which is a process with a durationof 10-30 minutes following a PEEP step. Even at fairly high PEEP levelsof approximately 12 cmH₂O, the end-expiratory esophageal pressureremains negative. The chest wall and diaphragm exert no, or very limitedpressure on the lung at end-expiratory pressure-volume equilibrium overa wide range of PEEP levels as a result of the rib cage end-expiratoryspring out force, which counteracts the recoil of the lung. The springout force of the rib cage retains the last part of the expiration andstretches the diaphragm, which limits abdominal hydrostatic pressureinfluence on the dependent lung.

A Lung Model Analog

A lung model covering the behavior of the respiratory system asdescribed in the present study, must encompass a lung with recoil, a ribcage with a spring out force, a fast and a slow abdominal hydrauliccompartment with a wall with structural elasticity. In FIG. 12, such alung model is described. FIG. 12 shows a schematic lung model with lungwith recoil and rib cage with a spring out force keeping the lung openat FRC. When the end-expiratory lung volume increases, the verticaldiameter of the rib cage increases and the diaphragm is stretched,thereby increasing the tension and the abdominal content is preventedfrom pressing direct on the lung, especially the dorsal parts. Thesurface of the slow abdominal compartment is around 7 dm2 and a caudaldisplacement corresponding to 0.5 L will raise the surface with lessthan 1 cm and the end-expiratory esophageal (pleural pressure) willincrease minimally following such a displacement of the diaphragm. Tidalvariations of esophageal pressure will reflect the fast compartment asthe inertia of the fluid and organs of the slow compartments will onlybe involved following a PEEP change.

Clinical Implications

The respiratory mechanical findings of this study indicate thatrecruitment is a much more time consuming process than previouslyenvisaged, where vital capacity recruitment maneuvers of less than 30seconds have been regarded as sufficient. Also, a recruitment maneuveraffects the chest wall to a high degree and it could be stated that notonly the lungs is recruited but to a large extent also the chest wall,which has a plasticity that makes it possible to increase thoraciccavity volume with limited esophageal pressure increase. A PEEP increaseseems to result in an opening up of the thoracic cavity, i.e. a caudaldisplacement of the diaphragm, preferential the non-dependent partsmaking room for an expansion of non-dependent lung. In this sense thePEEP increase does not primarily result in an opening of previouslycollapsed dependent lung but rather an expansion of already opennon-dependent lung.

Another possibly important clinical implication is the finding that theincrease in EELV following a PEEP increase can be predicted from themagnitude of change in PEEP and the lung elastance as ΔPEEP/EL. Thecorrelation coefficient is (r²=0.70) and the equation of the line of isclose to 1 (y=1.13x). The stress adaptation was related to the size ofthe PEEP step and lead to a great variability of the results, especiallyat PEEP steps of 8 and 12 cmH₂O. However, our results indicate that lungcompliance could be determined without esophageal pressure measurementsby measuring the change in end-expiratory lung volume and divide it bythe change in end-expiratory pressure, ΔEELV/ΔPEEP, as the PEEP increaseinduced change in transpulmonary pressure is closely related to thetidal transpulmonary pressure variation of a tidal volume of the samesize as the PEEP induced ΔEELV, see FIGS. 13 and 14.

FIG. 13 is a diagram comparing the change in transpulmonary pressure ofa tidal volume of the same size as the ΔEELV following a PEEP change andthe PEEP change.

FIG. 14 is a number of graphs in which it is compared to the change intranspulmonary pressure of a tidal volume of the same size as the ΔEELVfollowing a PEEP change. During abdominal loading the conventionaltranspulmonary pressure is lower than the ΔPEEP as the inertia of theabdominal cavity fluid and organs prevents a rapid displacement of thediaphragm. In contrast, the conventionally measured transpulmonarypressure is higher than the ΔPEEP during reverse Trendelenburg as thefluid and organs of the abdominal cavity are displaced in caudaldirection by gravity.

Using data from previously published studies, we performed a comparisonof conventionally determined (using esophageal pressure measurements)lung compliance in lung healthy patients and patients with moderate andsevere respiratory failure with determination of ΔEELV/ΔPEEP and found avery good correlation (r²=0.96), see Table 2 below.

Table 2 (below): Lung compliance in patients with ALI: Effects of PEEP.Based on data from Pelosi et al. Recruitment and derecruitment duringacute respiratory failure: an experimental study. Am J Respir Crit CareMed. 2001 Jul. 1; 164(1):122-30:

PEEP step, _(cmH) ₂ _(O) 0-5 5-10 10-15 Normal ΔEELV, _(ml) 516 515ΔEELV/ΔPEEP, _(ml/cmH) ₂ _(O) 103 103 C_(L) conventional, _(ml/cmH) ₂_(O) 108 112 Moderate ΔEELV, _(ml) 404 403 359 ΔEELV/ΔPEEP, _(ml/cmH) ₂_(O) 81 76 72 C_(L) conventional, _(ml/cmH) ₂ _(O) 72 76 65 ARDS ΔEELV,_(ml) 225 246 280 ΔEELV/ΔPEEP, _(ml/cmH) ₂ _(O) 45 49 56 C_(L)conventional, _(ml/cmH) ₂ _(O) 42 40 38

A comparison of transpulmonary pressure with data from patients withpulmonary and extrapulmonary ARDS also showed very good correlation,r²=0.991 see Table 3 below.

Conventional Method Lung Barometry PEEP EE PTP ΔPTP Total PTP EE PTPΔPTP Total PTP Pulmonary ARDS 0 0 14 14 0 16 16 5 4 14 19 5 17 22 10 915 23 10 19 29 15 12 18 31 15 20 35 Extrapulmonary ARDS 0 0 10 10 0 1313 5 3 9 13 5 10 15 10 8 9 16 10 10 20 15 12 8 20 15 9 24 EE =end-expiratory

Table 3 (above) Transpulmonary pressure (PTP) by conventional and LungBarometry based on data from Gattinoni et al “Acute respiratory distresssyndrome caused by pulmonary and extrapulmonary disease. Differentsyndromes?” Am J Respir Crit Care Med. 1998 July; 158(1):3-11.

In summary of the study, following an increase in PEEP there was asuccessive build-up of a new EELV. This was a process which occurredover several breaths. The results of the studies confirm thefeasibility, effect and efficiency of transpulmonary pressuredetermination. It was seen that a PEEP increase results in amulti-breath successively decreasing build-up of end-expiratory lungvolume. The number of breaths needed to reach this volume depends on therelation between chest wall and lung mechanics. Significantly lessbreaths are needed with higher lung vs chest wall elastance.End-expiratory esophageal pressure did not increase further after thefirst expiration following a PEEP increase (step) even thoughend-expiratory pressure continued to increase.

It is concluded that the balance between lung and chest wall elastancehas clear influence on PEEP induced inflation of the respiratory system.The increase in end expiratory lung volume was observed to be fairlyproportional to the magnitude of the PEEP step divided by lungelastance. In addition PEEP increase results in a less than expectedincrease in esophageal pressure indicating that the chest wall andabdomen gradually can accommodate changes in lung volume by stressadaptation and by the previously described rib cage end-expiratoryspring-out force which counteracts the recoil of the lung over a widerange of PEEP-levels.

These effects are regarded surprisingly and advantageous, encouragingdetermination of transpulmonary pressure and to separate lung and chestwall mechanics in a clinical setting, only using data available in theventilator.

The present invention has been described above with reference tospecific embodiments. However, other embodiments than the abovedescribed are equally possible within the scope of the invention.Different method steps than those described above, performing the methodby hardware or software, may be provided within the scope of theinvention. The different features and steps of the invention may becombined in other combinations than those described. The scope of theinvention is only limited by the appended patent claims.

The invention claimed is:
 1. A breathing apparatus comprising: an inspiratory valve, and a control unit that is adapted to determine a transpulmonary pressure (Ptp) in a patient connected to said breathing apparatus, wherein said control unit is configured to: set said breathing apparatus in a first mode of operation for ventilating said patient with a first Positive End Expiratory Pressure (PEEP) level by controlling said inspiratory valve and an expiratory valve; set said breathing apparatus in a second mode of operation for ventilating said patient with a second PEEP level starting from said first PEEP level, wherein said second PEEP level is based on a target PEEP level different from said first PEEP level, by controlling said inspiratory valve and said expiratory valve; determine a change in end-expiratory lung volume (ΔEELV) from a difference of end-expiratory lung volume (EELV) present at said first PEEP level and said second PEEP level, based on measurements from an inspiratory flow transducer and an expiratory flow transducer; and determine said Ptp based on said change in ΔEELV and a difference between said first PEEP level and said second PEEP level (ΔPEEP), measured by an expiratory pressure sensor.
 2. The apparatus of claim 1, wherein said control unit is configured to determine said Ptp when said second PEEP level is reached within a defined pressure threshold of said target PEEP level such that an equilibrium is established.
 3. The apparatus of claim 1, wherein said first PEEP is ambient pressure and said second PEEP is higher than said first PEEP; said first PEEP is higher than ambient pressure and said second PEEP is higher than said first pressure; or said first PEEP is higher than ambient pressure and said second PEEP is lower than said first PEEP.
 4. The apparatus of claim 1, wherein: said apparatus further comprises a user interface, setting said breathing apparatus in said second mode of operation is initiated from the user interface of said breathing apparatus, said control unit automatically determines said Ptp upon said initiation, and said automatic determination of Ptp is made during assisted and/or controlled ventilation of said patient by said apparatus.
 5. The apparatus of claim 1, wherein said control unit is configured to return said apparatus to said first mode of operation with a PEEP level of assisted controlled ventilation at said first PEEP level after determining said Ptp.
 6. The apparatus of claim 1, wherein said control unit is configured to stepwise increase PEEP from said first PEEP level until a sum of the stepwise obtained ΔEELV (ΣΔEELV) is substantially equal to a tidal volume at the first PEEP level.
 7. The apparatus of claim 1, wherein said control unit is configured to determine a non-linear lung compliance (C_(L)) and/or chest wall compliance (Ccw) by repeating PEEP level changes smaller than an initial difference between the first and second PEEP level and/or by reducing a tidal volume for detecting a deflection point or inflection point of the total compliance (C_(TOT)) or the lung compliance (C_(L)).
 8. The apparatus of claim 1, wherein said control unit is configured to adjust a PEEP level based on said determined Ptp by limiting a PEEP in mechanical ventilation provided by said apparatus to said patent to a lower level when a transpulmonary pressure is detected below a first threshold value to protect the lung from injury.
 9. The apparatus of claim 1, wherein said first and/or second mode of operation comprise at least one breathing cycle.
 10. The apparatus of claim 1, wherein said determination of Ptp comprises determination of separate resistive and elastic mechanical lung properties, such as lung compliance, and resistive and elastic mechanical chest wall properties, such as chest wall compliance.
 11. A method of internally, in a breathing apparatus according to claim 1, determining a transpulmonary pressure (Ptp) in a patient connected to the breathing apparatus by using a control unit, said method comprising: establishing a first Positive End Expiratory Pressure (PEEP) level; changing a target PEEP level from said first PEEP level to a second PEEP level, different from said first PEEP level; establishing said second PEEP level starting from said first PEEP level; determining a change in end-expiratory lung volume (ΔEELV) from a difference of an end-expiratory lung volume (EELV) present at said first PEEP level and said second PEEP level; and determining said Ptp based on said ΔEELV and a difference between said first PEEP level and said second PEEP level (APEEP).
 12. The method of claim 11, further comprising waiting until said second PEEP level is reached within a defined threshold such that an equilibrium is established.
 13. The method of claim 11, wherein said first PEEP is ambient pressure and said second PEEP is higher than said first PEEP; said first PEEP is higher than ambient pressure and said second PEEP is higher than said first PEEP; or said first PEEP is higher than ambient pressure and said second PEEP is lower than said first PEEP.
 14. The method of claim 11, wherein said method, is initiated by a user from a user interface of said breathing apparatus, and wherein said method automatically determines said Ptp upon initiation, and wherein said automatic determination is made during assisted and/or controlled ventilation of said patient by said breathing apparatus.
 15. The method of claim 11, and further comprising returning to said first PEEP level after said determination of Ptp.
 16. The method of any of claim 11, and further comprising determining a non-linear lung compliance C_(L) and/or chest wall compliance Ccw by repeating the method of claim 11 with PEEP level changes smaller than an initial difference between the first and second PEEP level; and/or reducing the tidal volume for detecting a deflection point of the total compliance C_(TOT); and/or stepwise increasing PEEP from said first PEEP level until a sum of the stepwise obtained ΔEELV (ΣΔEELV) is substantially equal to the tidal volume at the first PEEP level.
 17. The method of claim 15, wherein a C_(L) is determined by dividing ΔEELV by ΔPEEP.
 18. The method of claim 11, wherein ΔPEEP is directly determined from measurements of the expiratory pressure transducer at the first and second PEEP level.
 19. The method of claim 11, wherein ΔEELV is determined from spirometric measurements based on measurements of flow transducers in the breathing apparatus.
 20. The method of claim 11, further comprising determining a transpulmonary pressure difference (ΔPtp) based upon ΔPtp=ΔPaw×E_(L)/E_(TOT), wherein ΔPaw is the total respiratory system driving pressure determined from measurements by a pressure transducer of the breathing apparatus; E_(L) is Lung elastance; and E_(TOT) is total elastance determined from measurements of an inspiratory flow transducer and an inspiratory pressure transducer of said breathing apparatus.
 21. The method of claim 11, wherein said Ptp is determined without measuring an oesophagal pressure.
 22. The method of claim 11, and further comprising adjusting a PEEP level online during assisted and/or controlled ventilation of a patient, by a breathing apparatus based on the Ptp determined by limiting a PEEP level of said assisted controlled ventilation to a lower level when transpulmonary pressures are determined to be below a pre-determined first threshold value in order to protect the lung from injury.
 23. A computer-readable medium having embodied thereon a computer program for processing by a computer, wherein the computer program comprises a plurality of code segments for determining a transpulmonary pressure (Ptp) in a patient connected to a breathing apparatus, said code segments comprising: a first code segment for establishing a first Positive End Expiratory Pressure (PEEP) level; a second code segment for changing a target PEEP level from said first PEEP level to a second PEEP level, different from said first PEEP level, a third code segment for establishing said second PEEP level starting from said first PEEP level; a fourth code segment for determining a change in end-expiratory lung volume (ΔEELV) from a difference of end-expiratory lung volume (EELV) present at said first PEEP level and said second PEEP level; and a fifth code segment for determining said Ptp based on said change in ΔEELV and a difference between said first PEEP level and said second PEEP level (ΔPEEP). 